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The role of insulin/IGF-1 signaling in the longevity of model invertebrates, C. elegans and D. melanogaster
The role of insulin/IGF-1 signaling in the longevity of model invertebrates, C. elegans and D. melanogaster
BMB Reports. 2016. Feb, 49(2): 81-92
Copyright © 2016, Korean Society for Biochemistry and Molecular Biology
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Received : December 18, 2015
  • Published : February 29, 2016
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About the Authors
Ozlem Altintas
School of Interdisciplinary Bioscience and Bioengineering,
Sangsoon Park
Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Korea
Seung-Jae V. Lee
Information Technology Convergence Engineering, Pohang University of Science and Technology, Pohang 37673, Korea
seungjaelee@postech.ac.kr

Abstract
Insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway regulates aging in many organisms, ranging from simple invertebrates to mammals, including humans. Many seminal discoveries regarding the roles of IIS in aging and longevity have been made by using the roundworm Caenorhabditis elegans and the fruit fly Drosophila melanogaster . In this review, we describe the mechanisms by which various IIS components regulate aging in C. elegans and D. melanogaster . We also cover systemic and tissue-specific effects of the IIS components on the regulation of lifespan. We further discuss IIS-mediated physiological processes other than aging and their effects on human disease models focusing on C. elegans studies. As both C. elegans and D. melanogaster have been essential for key findings regarding the effects of IIS on organismal aging in general, these invertebrate models will continue to serve as workhorses to help our understanding of mammalian aging. [BMB Reports 2016; 49(2): 81-92]
Keywords
INTRODUCTION
The roundworm Caenorhabditis elegans and the fruit fly Drosophila melanogaster have been used as two most popular invertebrate models for studying aging and longevity (1 , 2) . In particular, their short lifespan together with their low cost and easy handling has established these invertebrates as excellent systems for research on molecular mechanisms regulating animal aging. Many important discoveries regarding evolutionarily conserved aging-regulatory pathways have been made using C. elegans and D. melanogaster . One of such pathways is the insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway, which was first shown to regulate longevity in C. elegans , and subsequently confirmed by using D. melanogaster . Importantly, the findings using these two invertebrate model organisms stimulated research on the role of IIS in mammalian aging, and led to discoveries showing that IIS also regulates aging in mammals, including mice and humans (3 , 4) . In this review, we will describe which components of IIS regulate lifespan, and how IIS modulates aging processes in these two model organisms. We will also review endocrine signaling and the importance of insulin-like peptides (ILPs) for systemic longevity regulation. Overall, our review will provide useful information regarding the conserved roles of IIS pathway in the aging of model organisms, which will eventually pave the way for understanding the mystery of human aging.
THE ROLE OF INSULIN/IGF-1 SIGNALING INC. elegansAGING
- Insulin/IGF-1 signaling pathway components that regulate the lifespan ofC. elegans
The insulin/IGF-1 signaling (IIS) pathway contains many evolutionarily conserved components that regulate aging ( Fig. 1 ). The gerontogenes daf-2 and age-1 encode the sole insulin/IGF-1 receptor and phosphatidylinositol-3-OH kinase (PI3K) (5 , 6) , respectively. DAF-2 and AGE-1 are two key upstream components of IIS that regulate various physiological aspects, including aging and adult lifespan. Two of the most important discoveries in the field of aging research were perhaps the findings demonstrating that inhibition of daf-2 or age-1 dramatically extended lifespan in C. elegans (7 - 9) . These discoveries stimulated many subsequent studies on the role of IIS in lifespan regulation, not only in C. elegans but also in D. melanogaster and mammals.
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Conserved longevity-regulatory components of insulin/IGF-1 signaling pathway in C. elegans and D. melanogaster. Insulin-like peptides (ILPs in Caenorhabditis elegans and DILPs in Drosophila melanogaster) bind to insulin/IGF-1 receptor (DAF-2 in C. elegans and dInR in D. melanogaster) and lead to its phosphorylation. Inhibition of insulin/IGF-1 receptor results in decreased binding to the insulin receptor substrate (IST-1 in C. elegans and CHICO in D. melanogaster), which in turn decreases the activity of phosphoinositide-3 kinase (AGE-1 in C. elegans and PI3K in D. melanogaster) that converts PIP2 to PIP3; conversely, the PTEN phosphatase (DAF-18 in C. elegans and dPTEN in D. melanogaster) functions to antagonize the activity of the phosphoinositide-3 kinase by converting PIP3 to PIP2. Decreased PIP3 levels lead to decreased activities of phosphoinositide-dependent kinase 1 (PDK-1 in C. elegans and dPDK1 in D. melanogaster) and the serine/threonine-specific protein kinase B (AKT-1/-2 in C. elegans and dAkt1 in D. melanogaster), and the activation of downstream transcription factor FOXO (DAF-16 in C. elegans and dFOXO in D. melanogaster). Reduced insulin/IGF-1 signaling in C. elegans also increases the activities of heat shock transcription factor-1 (HSF-1) and SKN-1 (NRF2). These transcription factors regulate the expression of target genes, which contribute to longevity.
IIS transduces signals through a combination of wellorganized sequential events, depending on environmental conditions. Under favorable conditions, IIS is activated and this confers normal development and adult lifespan. Specifically, agonist insulin-like peptides (ILPs) bind to their receptor, DAF-2, which in turn recruits an insulin receptor substrate (IRS)/IST-1 (10) . This leads to the activation of the AGE-1/PI3K, which increases the level of phosphatidylinositol (3 , 4 , 5) -trisphosphate (PIP 3 ) (5 , 11) ; this event is antagonistically balanced by DAF-18/PTEN phosphatase that promotes the conversion of PIP 3 to phosphatidylinositol (4 , 5) -bisphosphate (PIP 2 ) (12 - 19) . The signals provided by PIP 3 activate the downstream kinase cascade, composed of 3-phosphoinositide-dependent protein kinase 1 (PDK-1) (2) , protein kinase B (AKT-1/-2) (21) , and serum- and glucocorticoid-inducible kinase-1 (SGK-1) (22 ; but see also 23 , 24) . This in turn phosphorylates and inactivates DAF-16/FOXO transcription factor, by promoting its nucleusto-cytosol translocation (22 , 25 - 30) . Conversely, in unfavorable conditions, IIS is down-regulated and leads to the activation of DAF-16/FOXO via enhancing its translocation from the cytoplasm to the nucleus, where it switches on the expression of genes that promote longevity. Thus, C. elegans IIS pathway acts as a system in which many components transduce signals to modulate the aging processes, depending on extracellular conditions.
Three most important downstream lifespan-regulatory transcription factors of IIS that have been identified so far are DAF-16/FOXO, heat shock transcription factor 1 (HSF-1) and SKN-1/nuclear factor erythroid 2 (NRF2). DAF-16/FOXO regulates aging processes downstream of the canonical IIS cascade as described above. In addition, Jun-N-terminal kinase (JNK/JNK-1) (31) , AMP-activated protein kinase (AMPK/AAK-2) (32 - 34) , and Ste20-like protein kinase (MST1/CST-1) (35) activate DAF-16/FOXO via phosphorylation. Other non-kinase proteins have been shown to regulate C. elegans DAF-16/FOXO. A serine/threonine-protein phosphatase 4-regulatory subunit SMK-1 (36) , and an RNA helicase HEL-1 (37) , extend longevity by acting together with DAF-16/FOXO. DAF-16/FOXO is acetylated by an acetyl-transferase CBP-1/CREB binding protein (CBP), whose inhibition leads to constitutive nuclear localization of DAF-16/FOXO (38) . Host cell factor 1 (HCF-1) and enhancer of akt-1 null 7 (EAK-7) are other regulatory factors that inhibit DAF-16/FOXO activity without altering its subcellular localization (39 - 41) . DAF-16/FOXO also interacts with two highly homologous 14-3-3 protein family members, FTT-1/PAR-5 and FTT-2 (42 , 43) . The 14-3-3 proteins modulate the interaction between DAF-16/FOXO and other co-factors, such as SIR-2.1/sirtuin 1, an NAD-dependent deacetylase (42 , 44) . These diverse interactions and posttranslational modifications may help differentially regulate the activity of DAF-16/FOXO upon various environmental changes.
Downstream targets of DAF-16/FOXO were identified by using various approaches such as chromatin immunoprecipitation, bioinformatics, microarray and mRNA sequencing (31 , 45 - 51) . The DAF-16/FOXO target genes collectively contribute to longevity by enhancing cellular maintenance in animals with reduced IIS. Since many regulatory modes and targets of FOXO transcription factors are conserved among species, the longevity-regulatory modes of C. elegans DAF-16/FOXO are likely to be recapitulated in IIS-medicated longevity in mammals.
SKN-1, an oxidative stress-responsive NRF transcription factor, also contributes to the longevity conferred by reduced IIS (52 , 53) . Similar to DAF-16/FOXO, SKN-1 is sequestered in the cytoplasm by phosphorylation via the canonical IIS protein kinases, including AKT-1/-2 (52) . SKN-1 mediates the expression of genes involved in detoxification and stress responses (52 , 54 - 63) . Overexpression of constitutively nuclear SKN-1 extends lifespan in a DAF-16/FOXO-independent manner (52) . SKN-1 also promotes protein homeostasis through regulating proteasome production, which contributes to a longer lifespan (55 , 57 , 64) . In addition, SKN-1 promotes longevity of animals with reduced IIS through remodeling of extracellular matrix (65) .
HSF-1 is another important transcription factor acting downstream of IIS, and is essential for the longevity of animals with reduced IIS (66 - 70) . The function of HSF-1 in promoting longevity and reducing proteotoxicity is closely associated with the conserved IIS pathway. Genetic inhibition of hsf-1 accelerates tissue aging, thereby shortening the lifespan (71) . Knockdown of hsf-1 also suppresses the longevity phenotype of daf-2 and age-1 mutants; conversely, the overexpression of hsf-1 is sufficient to extend lifespan (51 , 66 , 67 , 69 , 72 , 73) . HSF-1 binds to specific regions of DNA containing heat shock elements (HSEs) (74 - 76) . The binding of HSF-1 to HSEs triggers the induction of genes encoding molecular chaperones, such as HSP-70 and HSP-16, whose overexpression extends lifespan (77 , 78) . Thus, HSF-1 appears to lead to longevity by upregulating the chaperone network that enhances the proper folding of various proteins (66 , 67) . DDL-1 (the C. elegans homolog of human coiled-coil domain-containing protein 53: CCDC53), DDL-2 (the C. elegans homolog of human Wiskott-Aldrich syndrome protein and SCAR homolog: WASH2), and HSB-1 (heat-shock factor binding protein-1), form a complex with HSF-1 and regulate lifespan by inhibiting the activity of HSF-1 (69) . Overall, HSF-1 and SKN-1 appear to promote longevity mainly through the induction of target genes that increase resistance to various stresses.
- Systemic regulation of insulin/IGF-1 signaling-mediated longevity inC. elegans
As the IIS pathway consists of many potential endocrine components, it is likely that IIS regulates lifespan in a systemic manner. The C. elegans genome encodes 40 ILPs, which appear to act as extracellular endocrine signals in C. elegans (79 , 80) . Functional studies on several ILPs, including ins-6 (81 , 82) , ins-7 (47 , 83 , 84) and daf-28 (80 , 85 , 86) , have been conducted. However, the majority of the 40 ILPs, which potentially regulate longevity and development, are yet to be characterized in detail. This is perhaps because many possible combinations of the interactions between ILPs and DAF-2/insulin/IGF-1 receptor make it difficult to dissect the specific functions of each ILP. A recent study indicates that ILPs can function in a combinatorial manner to coordinate various physiological processes (87) . This finding is different from the previous notion that ILPs generally confer a functional redundancy due to their structural similarities (79 , 80 , 88 - 91) . Therefore, some individuals or a group of ILPs may have a profound effect on longevity.
Most of the ILPs are expressed in neurons, although some ILPs are expressed in non-neuronal tissues such as hypodermis and intestine (79 - 83 , 88 - 90 , 92 - 94) . Overexpression of ins-7 in the intestine decreases the activity of DAF-16/FOXO in non-intestinal tissues and shortens lifespan (83) , suggesting an endocrine tissue-nonautonomous role of INS-7 in longevity. The expression of daf-2 in neurons is largely responsible for the longevity of daf-2 mutants (95 , 96) , pointing to the endocrine regulation of longevity by neuronal IIS. Together, it appears that IIS can systemically regulate lifespan from various tissues, via endocrine signaling.
- The role of insulin/IGF-1 signaling inC. elegansphysiology and age-related disease models
C. elegans that is exposed to unfavorable environmental conditions such as reduced food availability, extreme temperatures and a high population during development, enters an alternative diapause stage called dauer (97 , 98) . IIS is one of extensively studied signaling pathways that govern this dauer developmental decision ( Fig. 2 ). Genetic inhibition of daf-2 or age-1 , which extends adult lifespan, can cause constitutive dauer formation even under favorable conditions (97 , 98) . This dauer formation requires key downstream effectors in IIS, including DAF-18/PTEN and DAF-16/FOXO (97 , 98) . Reduced IIS activates a transcriptional program through DAF-16/FOXO, which leads to dauer formation. These findings raise the possibility that IIS may regulate dauer decision and lifespan using same effectors. However, the regulation of longevity and dauer formation by IIS can be uncoupled. Neuronal DAF-16/FOXO plays a more important role in the dauer decision than in lifespan regulation, whereas intestinal DAF-16/FOXO has a more profound effect on the lifespan extension than on the dauer decision (99) . In addition, IIS pathway regulates the lifespan exclusively during adulthood, while it regulates the dauer formation during early larval development (100) . Thus, spatiotemporal regulation of IIS differentially influences two separate aspects of animal physiology, development and adult lifespan.
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The role of insulin/IGF-1 signaling in C. elegans physiology and age-related disease models. Insulin/IGF-1 signaling (IIS) regulates dauer formation, stress resistance, and the models of age-related diseases in C. elegans. Reduced IIS promotes dauer formation and enhances resistance to various external and internal stresses, and pathogens. Inhibition of IIS also ameliorates defects associated with various human disease models. These protective effects of reduced IIS contribute to organismal longevity.
IIS also regulates resistance to a variety of stresses. C. elegans with reduced IIS displays enhanced resistance to environmental stresses such as oxidative stress ( Fig. 2 ) (52 , 101 - 103) , heat stress (104 - 106) , hypoxic stress (107 , 108) , osmotic stress (109 , 110) , ultraviolet (UV) stress (36 , 111) , and heavy metal toxicity (112) . Moreover, reduced IIS promotes better maintenance of internal homeostasis against cytosolic proteotoxicity (66 , 113) and endoplasmic reticulum (ER) stress (114) . The key downstream transcription factors of IIS that contribute to longevity, including DAF-16/FOXO (25 , 26 , 36 , 66 , 103 , 106 - 116) , HSF-1 (66 , 67) and SKN-1 (52 , 53) , regulate these stress resistance phenotypes as well. Thus, proper regulation of IIS is crucial for the protection of C. elegans from both external and internal stresses.
Bacteria serve as a major food source for C. elegans , and are likely to be abundant in the natural habitats of C. elegans , such as rotten fruits. Therefore, it seems likely that C. elegans constantly comes in contact with various bacterial species, which may include pathogenic bacteria. To combat infection by pathogens, C. elegans is equipped with an innate immune system, and IIS is one of the most prominent innate immune signaling pathways (117) . C. elegans with reduced IIS displays enhanced pathogen resistance, which is mediated by DAF-16/FOXO, HSF-1, and SKN-1 (84 , 118 - 122) . Reduced IIS leads to the induction of several antimicrobial genes (47) , and reduction in bacterial packing in the intestine (123) . Interestingly, Pseudomonas aeruginosa , a popular model bacterial pathogen in C. elegans , activates IIS to counteract the host immunity (124) . Therefore, IIS may be located at the front of constant battles between the host C. elegans and its bacterial pathogens
Because of its powerful genetics, C. elegans has also been widely used for modeling various human diseases, especially neurodegenerative diseases. The disease models of C. elegans were established by generating transgenic animals expressing various human disease-associated proteins; these include β-amyloid peptides (Aβ) for Alzheimer’s disease (125 - 127) , polyglutamine (polyQ) proteins for Huntington’s disease (128 - 132) , α-synuclein for Parkinson’s disease (133 - 137) , and a mutant superoxide dismutase 1 (SOD1) for amyotrophic lateral sclerosis (ALS) (138 - 141) . The Alzheimer’s disease model C. elegans , which expresses Aβ 1-42 in body wall muscles, is paralyzed and displays the accumulation of protein aggregates (68 , 125 , 142) . Reduced IIS relieves these phenotypes via activating DAF-16/FOXO and HSF-1 (68) , and inducing autophagic degradation of the protein aggregates (142) . Reduced IIS also suppresses the short lifespan of Aβ 1-42 -expressing animals (68) . The C. elegans model for Huntington’s disease has been widely used for studying proteotoxicity caused by aggregation of polyQ proteins (113 , 128 - 131 , 143 - 150) . The polyQ-expressing worms display progressive neurodegeneration, neuronal dysfunction, retarded development, and defective motility (113 , 128 - 131 , 143 - 150) . The daf-2 and age-1 mutations ameliorate a gradual age-dependent increase in toxicity resulting from polyQ aggregation through HSF-1 and DAF-16/FOXO (66 , 113 , 132 , 146 , 149) . Parkinson’s disease patients suffer from degeneration of dopaminergic neurons, which display accumulated protein inclusions that contain α-synuclein (151) . Similarly, the C. elegans models for Parkinson’s disease, which express wild-type or mutant human α-synuclein proteins in neurons, display the loss of dopaminergic neurons (133 , 134 , 137 , 152) . Reduced IIS by daf-2 mutations dramatically suppresses this neurodegeneration phenotype (152) . ALS, which is characterized by progressive motor neuron degeneration (153) , has also been studied using a C. elegans model (138 - 141) . Familial ALS is associated with mutations in the gene encoding SOD1 (154 , 155) . Neuronal expression of a mutant human SOD1 causes locomotion defects (140) and paralysis (141) in C. elegans . daf-2 mutations protect the ALS model worms from the paralysis (141) . Collectively, the results using C. elegans models indicate that IIS plays a crucial role in the pathophysiology of a majority of neurodegenerative diseases ( Fig. 2 ). These findings imply that IIS modulates protein homeostasis to regulate normal neuronal functions, which may be essential for a long and healthy life.
INSULIN/IGF-1 SIGNALING PATHWAY ANDDrosophila melanogasterAGING
- Insulin/IGF-1 signaling components implicated in the longevity ofD. melanogaster
The IIS pathway of Drosophila melanogaster consists of many components ( Fig. 1 ), including the insulin/IGF receptor (dInR), the insulin receptor substrate (CHICO), the phosphatidylinositol 3-kinase (PI3K) Dp110/p60, 3-phosphoinositide-dependent protein kinase 1 (dPDK1) and the protein kinase B (PKB), also known as dAkt1, and the transcription factor Drosophila FOXO (dFOXO) (156 - 171) . The activation mechanism of the IIS pathway in Drosophila has substantial similarities to that in C. elegans . Basically, the activation of dInR leads to up-regulation of a cascade of intracellular phosphorylation events, subsequently leading to the phosphorylation of dFOXO protein (160 - 162) . dInR conveys signals from Drosophila insulin-like peptides (DILPs), directly to PI3K or to CHICO, the insulin receptor substrate (156 , 172) . PI3K, which converts PIP 2 to PIP 3 , has a catalytic subunit, Dp110, and a regulatory subunit, Dp60 (158 , 159) . The action of PI3K is antagonized by the activity of dPTEN (173 - 175) , which catalyzes PIP 3 to PIP 2 . PIP 3 acts as an intracellular second messenger that activates a cascade of protein kinases, including dPDK1 and PKB/dAkt, which subsequently lead to the phosphorylation and the nuclear exclusion of dFOXO (162 , 170) . Conversely, reduced IIS through dInR or CHICO mutations, or overexpression of dPTEN , causes the translocation of dFOXO from the cytoplasm to the nucleus, where it up-regulates genes involved in longevity and stress resistance (160 , 162 , 176 , 177) .
In Drosophila , the IIS pathway regulates various physiological processes, including lifespan, stress responses, growth and development. Genetic inhibition of negative regulators of dFOXO, including several DILPs (178 , 179) , dInR (180) , the IRS/CHICO (181 , 182) , or 14-3-3 epsilon (183) , extends the lifespan of Drosophila . Conversely, overexpression of antagonistic IIS regulators, such as dPTEN or dFOXO, also extends the lifespan and/or delay heart aging (177 , 184 - 186 ; but see also 187) . Overall, these findings using Drosophila have remarkable similarities with those of C. elegans , highlighting the evolutionarily conserved nature of lifespan regulation by IIS components.
- Endocrine regulation of lifespan byDrosophilainsulin/IGF-1 signaling
The Drosophila melanogaster genome encodes eight DILPs (172 , 188 - 190) . The dilp genes display distinct temporal expression patterns. For example, dilp2 is expressed from embryo to adult stages, whereas dilp4 is expressed only during development prior to adulthood (172 , 179 , 191 - 195) . In addition, the expression sites of the eight dilp genes are diverse (196) . Notably, the major site of DILP production is the median neurosecretory cells (mNSCs) in the brain, also called insulin-producing cells (IPCs), where dilp1 , dilp2 , dilp3 and dilp5 are expressed (172 , 179 , 191 - 194) .
Cell non-autonomous regulation of lifespan by Drosophila IIS was proposed based on findings using tissue-specific overexpression of IIS components. Up-regulation of dFOXO in the adult head fat body is sufficient to promote longevity and oxidative stress resistance (177) . Muscle-specific overexpression of either dPTEN, dFOXO, or 4E-BP (a dFOXO target), also significantly increases lifespan (184) . The ablation of IPCs lengthens lifespan (179 , 197) , which corroborates the endocrine regulation of lifespan by IIS; this is also reminiscent of lifespan extension by the ablation of sensory neurons in C. elegans (reviewed in 198) . Among the DILPs expressed in the IPCs, DILP2 has been extensively explored for its implication in lifespan regulation, since it has the highest homology with human insulin (172 , 177 - 179 , 199 - 201) . The dilp2 null-mutant flies live long (178) , and the expression of dilp2 in the IPCs is reduced by the activation of dFOXO (177 , 199) . Therefore, Drosophila IIS appears to regulate the expression of DILPs and longevity via a feedback mechanism. Furthermore, reduced dilp2 expression and inhibited IIS in the fat body are associated with lifespan extension conferred by transgenic expression of a dominant-negative p53 (200) . DILP6, which is predominantly produced in the fat body, is another endocrine lifespan regulator (200 - 204) . Surprisingly, overexpression of dilp6 in the abdominal fat body leads to the repression of dilp2 in the brain, suggesting synergistic effects on lifespan regulation by a potential dInR antagonist DILP6 and an agonist DILP2 (204) . Collectively, lifespan regulation by IIS is controlled systemically by the action of DILPs that transmit signals, at least between the brain and fat body.
CONCLUSIONS
In this review, we have described findings regarding mechanisms by which IIS influences lifespan in two representative invertebrate models, C. elegans and D. melanogaster . The roles of many IIS components in aging are remarkably well conserved between C. elegans and D. melanogaster , and the intervention of the IIS leads to an extended lifespan in both animals. This suggests that the role of IIS in aging is likely to be conserved across phyla beyond these two species. Indeed, many findings using these invertebrate models have led to the discoveries demonstrating that changes in IIS can extend lifespan in mammals. For example, heterozygous IGF1 receptor- knockout mice ( Igf1r +/− ) live longer than wild-type (205) , and lower circulating IGF1 level correlates with mouse longevity (206) . In addition, genetic variants of IIS components, including IGF1 receptor and FOXO3A, are associated with human longevity (4 , 207) . Thus, the evidence for the evolutionarily conserved nature of IIS-mediated longevity is extremely strong, ranging from invertebrates to humans.
Both C. elegans and D. melanogaster have been invaluable for the identification of IIS components and their roles in aging at the organism level. Still, much remains to be discovered regarding the regulatory mechanisms of aging and longevity at the molecular level. As we can make new discoveries regarding organismal aging using these invertebrate models much faster than using vertebrates, C. elegans and D. melanogaster will continue to serve as indispensable tools for broadening our knowledge in aging. The progresses made by using these invertebrate models will eventually lead to the promotion of long and healthy human lives, and the prevention of age-associated diseases.
Acknowledgements
We thank the Lee laboratory members for critical comments on the manuscript. This work was supported by Basic Research Laboratory Grants NRF-2012R1A4A1028200 and NRF-2013R1A1A2014754 funded by the Korean Government (MSIP) through the National Research Foundation of Korea (NRF) to S-J.V.L.
References
Lee Y , An S , Artan M (2015) Genes and Pathways That Influence Longevity inCaenorhabditis elegans; in Aging Mechanisms, Mori N and Mook-Jung I (eds) Springer Japan 123 - 169
Giannakou ME , Partridge L (2007) Role of insulin-like signalling inDrosophilalifespan. Trends Biochem Sci 32 180 - 188    DOI : 10.1016/j.tibs.2007.02.007
Fontana L , Partridge L , Longo VD (2010) Extending healthy life span--from yeast to humans. Science 328 321 - 326    DOI : 10.1126/science.1172539
Kenyon CJ (2010) The genetics of ageing. Nature 464 504 - 512    DOI : 10.1038/nature08980
Morris JZ , Tissenbaum HA , Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause inCaenorhabditis elegans. Nature 382 536 - 539
Kimura KD , Tissenbaum HA , Liu Y , Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause inCaenorhabditis elegans. Science 277 942 - 946    DOI : 10.1126/science.277.5328.942
Friedman DB , Johnson TE 1988 A mutation in theage-1gene inCaenorhabditis eleganslengthens life and reduces hermaphrodite fertility. Genetics 118 75 - 86
Kenyon C , Chang J , Gensch E , Rudner A , Tabtiang R (1993) AC. elegansmutant that lives twice as long as wild type. Nature 366 461 - 464    DOI : 10.1038/366461a0
Klass MR (1983) A method for the isolation of longevity mutants in the nematodeCaenorhabditis elegansand initial results. Mech Ageing Dev 22 279 - 5/9    DOI : 10.1016/0047-6374(83)90082-9
Wolkow CA , Munoz MJ , Riddle DL , Ruvkun G (2002) Insulin receptor substrate and p55 orthologous adaptor proteins function in theCaenorhabditis elegansdaf-2/insulin-like signaling pathway. J Biol Chem 277 49591 - 49597    DOI : 10.1074/jbc.M207866200
Zhou K , Pandol S , Bokoch G , Traynor-Kaplan AE (1998) Disruption ofDictyosteliumPI3K genes reduces [32P]phosphatidylinositol 3,4 bisphosphate and [32P]phosphatidylinositol trisphosphate levels, alters F-actin distribution and impairs pinocytosis. J Cell Sci 111 (Pt 2) 283 - 294
Ogg S , Ruvkun G (1998) TheC. elegansPTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol Cell 2 887 - 893    DOI : 10.1016/S1097-2765(00)80303-2
Gil EB , Malone Link E , Liu LX , Johnson CD , Lees JA (1999) Regulation of the insulin-like developmental pathway ofCaenorhabditis elegansby a homolog of the PTEN tumor suppressor gene. Proc Natl Acad Sci U S A 96 2925 - 2930    DOI : 10.1073/pnas.96.6.2925
Mihaylova VT , Borland CZ , Manjarrez L , Stern MJ , Sun H (1999) The PTEN tumor suppressor homolog inCaenorhabditis elegansregulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc Natl Acad Sci U S A 96 7427 - 7432    DOI : 10.1073/pnas.96.13.7427
Rouault JP , Kuwabara PE , Sinilnikova OM , Duret L , Thierry-Mieg D , Billaud M (1999) Regulation of dauer larva development inCaenorhabditis elegansbydaf-18, a homologue of the tumour suppressor PTEN. Curr Biol 9 329 - 332    DOI : 10.1016/S0960-9822(99)80143-2
Dorman JB , Albinder B , Shroyer T , Kenyon C (1995) Theage-1anddaf-2genes function in a common pathway to control the lifespan ofCaenorhabditis elegans. Genetics 141 1399 - 1406
Larsen PL , Albert PS , Riddle DL (1995) Genes that regulate both development and longevity inCaenorhabditis elegans. Genetics 139 1567 - 1583
Gottlieb S , Ruvkun G (1994) daf-2, daf-16anddaf-23: genetically interacting genes controlling Dauer formation inCaenorhabditis elegans. Genetics 137 107 - 120
Solari F , Bourbon-Piffaut A , Masse I , Payrastre B , Chan AM , Billaud M (2005) The human tumour suppressor PTEN regulates longevity and dauer formation inCaenorhabditis elegans. Oncogene 24 20 - 27    DOI : 10.1038/sj.onc.1207978
Paradis S , Ailion M , Toker A , Thomas JH , Ruvkun G (1999) A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause inCaenorhabditis elegans. Genes Dev 13 1438 - 1452    DOI : 10.1101/gad.13.11.1438
Paradis S , Ruvkun G (1998) Caenorhabditis elegansAkt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12 2488 - 2498    DOI : 10.1101/gad.12.16.2488
Hertweck M , Gobel C , Baumeister R (2004) C. elegansSGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev Cell 6 577 - 588    DOI : 10.1016/S1534-5807(04)00095-4
Chen AT , Guo C , Dumas KJ , Ashrafi K , Hu PJ (2013) Effects ofCaenorhabditis elegans sgk-1mutations on lifespan, stress resistance, and DAF-16/FoxO regulation. Aging Cell 12 932 - 940    DOI : 10.1111/acel.12120
Xiao R , Zhang B , Dong Y (2013) A genetic program promotesC. eleganslongevity at cold temperatures via a thermosensitive TRP channel. Cell 152 806 - 817    DOI : 10.1016/j.cell.2013.01.020
Henderson ST , Johnson TE (2001) daf-16integrates developmental and environmental inputs to mediate aging in the nematodeCaenorhabditis elegans. Curr Biol 11 1975 - 1980    DOI : 10.1016/S0960-9822(01)00594-2
Lee RY , Hench J , Ruvkun G (2001) Regulation ofC. elegansDAF-16 and its human ortholog FKHRL1 by thedaf-2insulin-like signaling pathway. Curr Biol 11 1950 - 1957    DOI : 10.1016/S0960-9822(01)00595-4
Lin K , Hsin H , Libina N , Kenyon C (2001) Regulation of theCaenorhabditis eleganslongevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28 139 - 145    DOI : 10.1038/88850
Cahill CM , Tzivion G , Nasrin N (2001) Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA binding and function via 14-3-3-dependent and 14-3-3-independent pathways. J Biol Chem 276 13402 - 13410    DOI : 10.1074/jbc.M010042200
Ogg S , Paradis S , Gottlieb S (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals inC. elegans. Nature 389 994 - 999    DOI : 10.1038/40194
Lin K , Dorman JB , Rodan A , Kenyon C (1997) daf-16: An HNF-3/forkhead family member that can function to double the life-span ofCaenorhabditis elegans. Science 278 1319 - 1322    DOI : 10.1126/science.278.5341.1319
Oh SW , Mukhopadhyay A , Svrzikapa N , Jiang F , Davis RJ , Tissenbaum HA (2005) JNK regulates lifespan inCaenorhabditis elegansby modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc Natl Acad Sci U S A 102 4494 - 4499    DOI : 10.1073/pnas.0500749102
Curtis R , O G , DiStefano PS (2006) Aging networks inCaenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5 119 - 126    DOI : 10.1111/j.1474-9726.2006.00205.x
Greer EL , Dowlatshahi D , Banko MR (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction inC. elegans. elegans. Curr Biol 17 1646 - 1656    DOI : 10.1016/j.cub.2007.08.047
Apfeld J , O G , McDonagh T , DiStefano PS , Curtis R (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan inC. elegans. Genes Dev 18 3004 - 3009    DOI : 10.1101/gad.1255404
Lehtinen MK , Yuan Z , Boag PR (2006) A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125 987 - 1001    DOI : 10.1016/j.cell.2006.03.046
Wolff S , Ma H , Burch D , Maciel GA , Hunter T , Dillin A (2006) SMK-1, an essential regulator of DAF-16-mediated longevity. Cell 124 1039 - 1053    DOI : 10.1016/j.cell.2005.12.042
Seo M , Seo K , Hwang W (2015) RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling inCaenorhabditis elegans. Proc Natl Acad Sci U S A 112 E4246 - E4255    DOI : 10.1073/pnas.1505451112
Chiang WC , Tishkoff DX , Yang B (2012) C. elegansSIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. PLoS Genet 8 e1002948 -    DOI : 10.1371/journal.pgen.1002948
Hu PJ , Xu J , Ruvkun G (2006) Two membrane-associated tyrosine phosphatase homologs potentiateC. elegansAKT-1/PKB signaling. PLoS Genet 2 e99 -    DOI : 10.1371/journal.pgen.0020099
Li J , Ebata A , Dong Y , Rizki G , Iwata T , Lee SS (2008) Caenorhabditis elegansHCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol 6 e233 -    DOI : 10.1371/journal.pbio.0060233
Alam H , Williams TW , Dumas KJ (2010) EAK-7 controls development and life span by regulating nuclear DAF-16/FoxO activity. Cell Metab 12 30 - 41    DOI : 10.1016/j.cmet.2010.05.004
Berdichevsky A , Viswanathan M , Horvitz HR , Guarente L (2006) C. elegansSIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 125 1165 - 1177    DOI : 10.1016/j.cell.2006.04.036
Li J , Tewari M , Vidal M , Lee SS (2007) The 14-3-3 protein FTT-2 regulates DAF-16 inCaenorhabditis elegans. Dev Biol 301 82 - 91    DOI : 10.1016/j.ydbio.2006.10.013
Wang Y , Oh SW , Deplancke B , Luo J , Walhout AJ , Tissenbaum HA (2006) C. elegans14-3-3 proteins regulate life span and interact with SIR-2.1 and DAF-16/FOXO. Mech Ageing Dev 127 741 - 747    DOI : 10.1016/j.mad.2006.05.005
Lee SS , Kennedy S , Tolonen AC , Ruvkun G (2003) DAF-16 target genes that controlC. eleganslife-span and metabolism. Science 300 644 - 647    DOI : 10.1126/science.1083614
Ookuma S , Fukuda M , Nishida (2003) Identification of a DAF-16 transcriptional target gene,scl-1, that regulates longevity and stress resistance inCaenorhabditis elegans. Curr Biol 13 427 - 431    DOI : 10.1016/S0960-9822(03)00108-8
Murphy CT , McCarroll SA , Bargmann CI (2003) Genes that act downstream of DAF-16 to influence the lifespan ofCaenorhabditis elegans. Nature 424 277 - 283    DOI : 10.1038/nature01789
McElwee J , Bubb K , Thomas JH (2003) Transcriptional outputs of theCaenorhabditis elegansforkhead protein DAF-16. Aging Cell 2 111 - 121    DOI : 10.1046/j.1474-9728.2003.00043.x
Golden TR , Melov S (2004) Microarray analysis of gene expression with age in individual nematodes. Aging Cell 3 111 - 124    DOI : 10.1111/j.1474-9728.2004.00095.x
Halaschek-Wiener J , Khattra JS , McKay S (2005) Analysis of long-lived C Genome Res 15 603 - 615    DOI : 10.1101/gr.3274805
Lee SJ , Murphy CT , Kenyon C (2009) Glucose shortens the life span ofC. elegansby downregulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab 10 379 - 391    DOI : 10.1016/j.cmet.2009.10.003
Tullet JM , Hertweck M , An JH (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling inC. elegans Cell 132 1025 - 1038    DOI : 10.1016/j.cell.2008.01.030
An JH , Blackwell TK (2003) SKN-1 linksC. elegansmesendodermal specification to a conserved oxidative stress response. Genes Dev 17 1882 - 1893    DOI : 10.1101/gad.1107803
An JH , Vranas K , Lucke M (2005) Regulation of theCaenorhabditis elegansoxidative stress defense protein SKN-1 by glycogen synthase kinase-3. Proc Natl Acad Sci U S A 102 16275 - 16280    DOI : 10.1073/pnas.0508105102
Kahn NW , Rea SL , Moyle S , Kell A , Johnson TE (2008) Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidativestress response inCaenorhabditis elegans. Biochem J 409 205 - 213    DOI : 10.1042/BJ20070521
Oliveira RP , Porter Abate J , Dilks K (2009) Condition-adapted stress and longevity gene regulation byCaenorhabditis elegansSKN-1/Nrf. Aging Cell 8 524 - 541    DOI : 10.1111/j.1474-9726.2009.00501.x
Wang J , Robida-Stubbs S , Tullet JM , Rual JF , Vidal M , Blackwell TK (2010) RNAi screening implicates a SKN-1-dependent transcriptional response in stress resistance and longevity deriving from translation inhibition. PLoS Genet 6 e1001048 -    DOI : 10.1371/journal.pgen.1001048
Staab TA , Griffen TC , Corcoran C , Evgrafov O , Knowles JA , Sieburth D 2013 The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function inCaenorhabditis elegans. PLoS Genet 9 e1003354 -    DOI : 10.1371/journal.pgen.1003354
Glover-Cutter KM , Lin S , Blackwell TK (2013) Integration of the unfolded protein and oxidative stress responses through SKN-1/Nrf. PLoS Genet 9 e1003701 -    DOI : 10.1371/journal.pgen.1003701
Choe KP , Przybysz AJ , Strange K e1003701 The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 inCaenorhabditis elegans. Mol Cell Biol 29 2704 - 2715    DOI : 10.1128/MCB.01811-08
Park SK , Tedesco PM , Johnson TE (2009) Oxidative stress and longevity inCaenorhabditis elegansas mediated by SKN-1. Aging Cell 8 258 - 269    DOI : 10.1111/j.1474-9726.2009.00473.x
Pang S , Lynn DA , Lo JY , Paek J , Curran SP (2014) SKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation. Nat Commun 5 5048 -    DOI : 10.1038/ncomms6048
Kell A , Ventura N , Kahn N , Johnson TE (2007) Activation of SKN-1 by novel kinases inCaenorhabditis elegans. Free Radic Biol Med 43 1560 - 1566    DOI : 10.1016/j.freeradbiomed.2007.08.025
Li X , Matilainen O , Jin C , Glover-Cutter KM , Holmberg CI , Blackwell TK (2011) Specific SKN-1/Nrf stress responses to perturbations in translation elongation and proteasome activity. PLoS Genet 7 e1002119 -
Ewald CY , Landis JN , Porter Abate J , Murphy CT , Blackwell TK (2015) Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. Nature 519 97 - 101    DOI : 10.1038/nature14021
Hsu AL , Murphy CT , Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300 1142 - 1145    DOI : 10.1126/science.1083701
Morley JF , Morimoto RI (2004) Regulation of longevity inCaenorhabditis elegansby heat shock factor and molecular chaperones. Mol Biol Cell 15 657 - 664    DOI : 10.1091/mbc.E03-07-0532
Cohen E , Bieschke J , Perciavalle RM , Kelly JW , Dillin A (2006) Opposing activities protect against age-onset proteotoxicity. Science 313 1604 - 1610
Chiang WC , Ching TT , Lee HC , Mousigian C , Hsu AL (2012) HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity. Cell 148 322 - 334    DOI : 10.1016/j.cell.2011.12.019
Seo K , Choi E , Lee D , Jeong DE , Jang SK , Lee SJ (2013) Heat shock factor 1 mediates the longevity conferred by inhibition of TOR and insulin/IGF-1 signaling pathways inC. elegans. Aging Cell 12 1073 - 1081    DOI : 10.1111/acel.12140
Garigan D , Hsu AL , Fraser AG , Kamath RS , Ahringer J , Kenyon C (2002) Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161 1101 - 1112
Douglas PM , Baird NA , Simic MS (2015) Heterotypic signals from neural HSF-1 separate thermotolerance from longevity. Cell Rep 12 1196 - 1204    DOI : 10.1016/j.celrep.2015.07.026
Baird NA , Douglas PM , Simic MS (2015) HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span. Science 346 360 - 363    DOI : 10.1126/science.1253168
Amin J , Ananthan J , Voellmy R (1988) Key features of heat shock regulatory elements. Mol Cell Biol 8 3761 - 3769    DOI : 10.1128/MCB.8.9.3761
Kay RJ , Boissy RJ , Russnak RH , Candido EP (1986) Efficient transcription of aCaenorhabditis elegansheat shock gene pair in mouse fibroblasts is dependent on multiple promoter elements which can function bidirectionally. Mol Cell Biol 6 3134 - 3143    DOI : 10.1128/MCB.6.9.3134
Russnak RH , Candido EP (1985) Locus encoding a family of small heat shock genes inCaenorhabditis elegans: two genes duplicated to form a 3.8-kilobase inverted repeat. Mol Cell Biol 5 1268 - 1278    DOI : 10.1128/MCB.5.6.1268
Yokoyama K , Fukumoto K , Murakami T (2002) Extended longevity ofCaenorhabditis elegansby knocking in extra copies of hsp70F, a homolog of mot-2 (mortalin)/mthsp70/Grp75. FEBS Lett 516 53 - 57
Walker GA , Lithgow GJ (2003) Lifespan extension inC. elegansby a molecular chaperone dependent upon insulin-like signals. Aging Cell 2 131 - 139    DOI : 10.1046/j.1474-9728.2003.00045.x
Pierce SB , Costa M , Wisotzkey R 2001 Regulation of DAF-2 receptor signaling by human insulin andins-1, a member of the unusually large and diverseC. elegansinsulin gene family. Genes Dev 15 672 - 686    DOI : 10.1101/gad.867301
Li W , Kennedy SG , Ruvkun G (2003) daf-28encodes aC. elegansinsulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev 17 844 - 858    DOI : 10.1101/gad.1066503
Chen Z , Hendricks M , Cornils A , Maier W , Alcedo J , Zhang Y (2013) Two insulin-like peptides antagonistically regulate aversive olfactory learning inC. elegans. Neuron 77 572 - 585    DOI : 10.1016/j.neuron.2012.11.025
Cornils A , Gloeck M , Chen Z , Zhang Y , Alcedo J (2011) Specific insulin-like peptides encode sensory information to regulate distinct developmental processes. Development 138 1183 - 1193    DOI : 10.1242/dev.060905
Murphy CT , Lee SJ , Kenyon C (2007) Tissue entrainment by feedback regulation of insulin gene expression in the endoderm ofCaenorhabditis elegans. Proc Natl Acad Sci U S A 104 19046 - 19050    DOI : 10.1073/pnas.0709613104
Kawli T , Tan MW (2008) Neuroendocrine signals modulate the innate immunity ofCaenorhabditis elegansthrough insulin signaling. Nat Immunol 9 1415 - 1424    DOI : 10.1038/ni.1672
Malone EA , Inoue T , Thomas JH (1996) Genetic analysis of the roles ofdaf-28andage-1in regulatingCaenorhabditis elegansdauer formation. Genetics 143 1193 - 1205
Malone EA , Thomas JH (1994) A screen for nonconditional dauer-constitutive mutations inCaenorhabditis elegans. Genetics 136 879 - 886
Fernandes de Abreu DA , Caballero A , Fardel P (2014) An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology. PLoS Genet 10 e1004225 -    DOI : 10.1371/journal.pgen.1004225
Ritter AD , Shen Y , Fuxman Bass J (2013) Complex expression dynamics and robustness inC. elegansinsulin networks. Genome Res 23 954 - 965    DOI : 10.1101/gr.150466.112
Hung WL , Wang Y , Chitturi J , Zhen M (2014) ACaenorhabditis elegansdevelopmental decision requires insulin signaling-mediated neuron-intestine communication. Development 141 1767 - 1779    DOI : 10.1242/dev.103846
Chen Y , Baugh LR (2014) Ins-4anddaf-28function redundantly to regulateC. elegansL1 arrest. Dev Biol 394 314 - 326    DOI : 10.1016/j.ydbio.2014.08.002
Duret L , Guex N , Peitsch MC , Bairoch A (1998) New insulin-like proteins with atypical disulfide bond pattern characterized inCaenorhabditis elegansby comparative sequence analysis and homology modeling. Genome Res 8 348 - 353
Michaelson D , Korta DZ , Capua Y , Hubbard EJ (2010) Insulin signaling promotes germline proliferation inC. elegans. Development 137 671 - 680    DOI : 10.1242/dev.042523
Leinwand SG , Chalasani SH (2013) Neuropeptide signaling remodels chemosensory circuit composition inCaenorhabditis elegans. Nat Neurosci 16 1461 - 1467    DOI : 10.1038/nn.3511
Ohta A , Ujisawa T , Sonoda S , Kuhara A (2014) Light and pheromone-sensing neurons regulates cold habituation through insulin signalling inCaenorhabditis elegans. Nat Commun 5 4412 -
Wolkow CA , Kimura KD , Lee MS , Ruvkun G (2000) Regulation ofC. eleganslife-span by insulinlike signaling in the nervous system. Science 290 147 - 150    DOI : 10.1126/science.290.5489.147
Iser WB , Gami MS , Wolkow CA (2007) Insulin signaling inCaenorhabditis elegansregulates both endocrine-like and cell-autonomous outputs. Dev Biol 303 434 - 447    DOI : 10.1016/j.ydbio.2006.04.467
Hu PJ (2007) Dauer. WormBook: the online review ofC. elegansbiology 1 - 19
Riddle DL , Albert PS (1997) Genetic and Environmental Regulation of Dauer Larva Development; inC. elegansII, Riddle DL, Blumenthal T, Meyer BJ et al (eds) Cold Spring Harbor Laboratory Press Cold Spring Harbor (NY)
Libina N , Berman JR , Kenyon C (2003) Tissue-specific activities ofC. elegansDAF-16 in the regulation of lifespan. Cell 115 489 - 502    DOI : 10.1016/S0092-8674(03)00889-4
Dillin A , Crawford DK , Kenyon C (2002) Timing requirements for insulin/IGF-1 signaling inC. elegans. Science 298 830 - 834    DOI : 10.1126/science.1074240
Larsen PL (1993) Aging and resistance to oxidative damage inCaenorhabditis elegans. Proc Natl Acad Sci U S A 90 8905 - 8909    DOI : 10.1073/pnas.90.19.8905
Vanfleteren JR (1993) Oxidative stress and ageing inCaenorhabditis elegans. Biochem J 292 (Pt 2) 605 - 608    DOI : 10.1042/bj2920605
Honda Y , Honda S (1999) Thedaf-2gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression inCaenorhabditis elegans. FASEB J 13 1385 - 1393
Gems D , Sutton AJ , Sundermeyer ML (1998) Two pleiotropic classes ofdaf-2mutation affect larval arrest, adult behavior, reproduction and longevity inCaenorhabditis elegans. Genetics 150 129 - 155
Lithgow GJ , White TM , Melov S , Johnson TE (1995) Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci U S A 92 7540 - 7544    DOI : 10.1073/pnas.92.16.7540
McColl G , Rogers AN , Alavez S (2010) Insulin-like signaling determines survival during stress via posttranscriptional mechanisms inC. elegans. Cell Metab 12 260 - 272    DOI : 10.1016/j.cmet.2010.08.004
Scott BA , Avidan MS , Crowder CM (2002) Regulation of hypoxic death inC. elegansby the insulin/IGF receptor homolog DAF-2. Science 296 2388 - 2391    DOI : 10.1126/science.1072302
Mabon ME , Scott BA , Crowder CM (2009) Divergent mechanisms controlling hypoxic sensitivity and lifespan by the DAF-2/insulin/IGF-receptor pathway. PLoS One 4 e7937 -    DOI : 10.1371/journal.pone.0007937
Lamitina ST , Strange K (2005) Transcriptional targets of DAF-16 insulin signaling pathway protectC. elegansfrom extreme hypertonic stress. Am J Physiol Cell Physiol 288 C467 - C474    DOI : 10.1152/ajpcell.00451.2004
Burkewitz K , Choe K , Strange K (2011) Hypertonic stress induces rapid and widespread protein damage inC. elegans. Am J Physiol Cell Physiol 301 C566 - C576    DOI : 10.1152/ajpcell.00030.2011
Murakami S , Johnson TE (1996) A genetic pathway conferring life extension and resistance to UV stress inCaenorhabditis elegans. Genetics 143 1207 - 1218
Barsyte D , Lovejoy DA , Lithgow GJ (2001) Longevity and heavy metal resistance indaf-2andage-1long-lived mutants ofCaenorhabditis elegans. FASEB J 15 627 - 634    DOI : 10.1096/fj.99-0966com
Morley JF , Brignull HR , Weyers JJ , Morimoto RI (2002) The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging inCaenorhabditis elegans. Proc Natl Acad Sci U S A 99 10417 - 10422    DOI : 10.1073/pnas.152161099
Henis-Korenblit S , Zhang PC , Hansen M (2010) Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci U S A 107 9730 - 9735    DOI : 10.1073/pnas.1002575107
Essers MA , de Vries-Smits LM , Barker N , Polderman PE , Burgering BM , Korswagen HC (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308 181 - 1184    DOI : 10.1126/science.1109083
Mueller MM , Castells-Roca L , Babu V (2014) DAF-16/FOXO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage. Nat Cell Biol 16 1168 - 1179    DOI : 10.1038/ncb3071
Ermolaeva MA , Schumacher B (2014) Insights from the worm: theC. elegansmodel for innate immunity. Semin Immunol 26 303 - 309    DOI : 10.1016/j.smim.2014.04.005
Garsin DA , Villanueva JM , Begun J (2003) Long-livedC. elegansdaf-2mutants are resistant to bacterial pathogens. Science 300 1921 -    DOI : 10.1126/science.1080147
Kerry S , TeKippe M , Gaddis NC , Aballay A (2006) GATA transcription factor required for immunity to bacterial and fungal pathogens. PLoS One 1 e77 -    DOI : 10.1371/journal.pone.0000077
Singh V , Aballay A (2006) Heat-shock transcription factor (HSF)-1 pathway required forCaenorhabditis elegansimmunity. Proc Natl Acad Sci U S A 103 13092 - 13097    DOI : 10.1073/pnas.0604050103
Papp D , Csermely P , Soti C (2012) A role for SKN-1/Nrf in pathogen resistance and immunosenescence inCaenorhabditis elegans. PLoS Pathog 8 e1002673 -    DOI : 10.1371/journal.ppat.1002673
Evans EA , Chen WC , Tan MW (2008) The DAF-2 insulin-like signaling pathway independently regulates aging and immunity inC. elegans. Aging Cell 7 879 - 893    DOI : 10.1111/j.1474-9726.2008.00435.x
Portal-Celhay C , Bradley ER , Blaser MJ (2012) Control of intestinal bacterial proliferation in regulation of lifespan inCaenorhabditis elegans. BMC Micobiol 12 49 -    DOI : 10.1186/1471-2180-12-49
Evans EA , Kawli T , Tan M-W (2008) Pseudomonas aeruginosa suppresses host immunity by activating the DAF-2 insulin-like signaling pathway inCaenorhabditis elegans. PLoS Pathog 4 e1000175 -    DOI : 10.1371/journal.ppat.1000175
Link CD (1995) Expression of human β-amyloid peptide in transgenicCaenorhabditis elegans. Proc Natl Acad Sci U S A 92 9368 - 9372    DOI : 10.1073/pnas.92.20.9368
Fay DS , Fluet A , Johnson CJ , Link CD (1998) In Vivo Aggregation of β‐Amyloid Peptide Variants. J Neurochem 71 1616 - 1625    DOI : 10.1046/j.1471-4159.1998.71041616.x
Link CD , Taft A , Kapulkin V (2003) Gene expression analysis in a transgenicCaenorhabditis elegansAlzheimer’s disease model. Neurobiol Aging 24 397 - 413    DOI : 10.1016/S0197-4580(02)00224-5
Faber PW , Alter JR , MacDonald ME , Hart AC (1999) Polyglutamine-mediated dysfunction and apoptotic death of aCaenorhabditis eleganssensory neuron. Proc Natl Acad Sci U S A 96 179 - 184    DOI : 10.1073/pnas.96.1.179
Satyal SH , Schmidt E , Kitagawa K (2000) Polyglutamine aggregates alter protein folding homeostasis inCaenorhabditis elegans. Proc Natl Acad Sci U S A 97 5750 - 5755    DOI : 10.1073/pnas.100107297
Parker JA , Connolly JB , Wellington C , Hayden M , Dausset J , Neri C (2001) Expanded polyglutamines inCaenorhabditis eleganscause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death. Proc Natl Acad Sci U S A 98 13318 - 13323    DOI : 10.1073/pnas.231476398
Brignull HR , Moore FE , Tang SJ , Morimoto RI (2006) Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronalCaenorhabditis elegansmodel. J Neurosci 26 7597 - 7606    DOI : 10.1523/JNEUROSCI.0990-06.2006
Mohri-Shiomi A , Garsin DA (2008) Insulin signaling and the heat shock response modulate protein homeostasis in theCaenorhabditis elegansintestine during infection. J Biol Chem 283 194 - 201    DOI : 10.1074/jbc.M707956200
Lakso M , Vartiainen S , Moilanen AM (2003) Dopaminergic neuronal loss and motor deficits inCaenorhabditis elegansoverexpressing human alpha-synuclein. J Neurochem 86 165 - 172    DOI : 10.1046/j.1471-4159.2003.01809.x
Cao S , Gelwix CC , Caldwell KA , Caldwell GA (2005) Torsin-mediated protection from cellular stress in the dopaminergic neurons ofCaenorhabditis elegans. J Neurosci 25 3801 - 3812    DOI : 10.1523/JNEUROSCI.5157-04.2005
Kuwahara T , Koyama A , Gengyo-Ando K (2006) Familial Parkinson mutant α-synuclein causes dopamine neuron dysfunction in transgenicCaenorhabditis elegans. J Biol Chem 281 334 - 340    DOI : 10.1074/jbc.M504860200
Kuwahara T , Koyama A , Koyama S (2008) A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in ^-synuclein transgenicC. elegans. Hum Mol Genet 17 2997 - 3009    DOI : 10.1093/hmg/ddn198
Hamamichi S , Rivas RN , Knight AL , Cao S , Caldwell KA , Caldwell GA (2008) Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model. Proc Natl Acad Sci U S A 105 728 - 733    DOI : 10.1073/pnas.0711018105
Oeda T , Shimohama S , Kitagawa N (2001) Oxidative stress causes abnormal accumulation of familial amyotrophic lateral sclerosis-related mutant SOD1 in transgenicCaenorhabditis elegans. Hum Mol Genet 10 203 - 2023    DOI : 10.1093/hmg/10.19.2013
Gidalevitz T , Krupinski T , Garcia S , Morimoto RI (2009) Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity. PLoS Genet 5 e1000399 -    DOI : 10.1371/journal.pgen.1000399
Wang J , Farr GW , Hall DH (2009) An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons ofCaenorhabditis elegans. PLoS Genet 5 e1000350 -    DOI : 10.1371/journal.pgen.1000350
Li J , Huang KX , Le WD (2013) Establishing a novelC. elegansmodel to investigate the role of autophagy in amyotrophic lateral sclerosis. Acta Pharmacol Sin 34 644 - 650    DOI : 10.1038/aps.2012.190
Florez-McClure ML , Hohsfield LA , Fonte G , Bealor MT , Link CD (2007) Decreased insulin-receptor signaling promotes the autophagic degradation of β-amyloid peptide inC. elegans. Autophagy 3 569 - 580    DOI : 10.4161/auto.4776
David DC , Ollikainen N , Trinidad JC , Cary MP , Burlingame AL , Kenyon C (2010) Widespread protein aggregation as an inherent part of aging inC. elegans. PLoS Biol 8 e1000450 -    DOI : 10.1371/journal.pbio.1000450
Wang H , Lim PJ , Yin C , Rieckher M , Vogel BE , Monteiro MJ (2006) Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin. Hum Mol Genet 15 1025 - 1041    DOI : 10.1093/hmg/ddl017
Wang H , Lim PJ , Karbowski M , Monteiro MJ (2009) Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet 18 737 - 752    DOI : 10.1093/hmg/ddn404
Steinkraus KA , Smith ED , Davis C (2008) Dietary restriction suppresses proteotoxicity and enhances longevity by anhsf-1-dependent mechanism inCaenorhabditis elegans. Aging Cell 7 394 - 404    DOI : 10.1111/j.1474-9726.2008.00385.x
Faber PW , Voisine C , King DC , Bates EA , Hart AC (2002) Glutamine/proline-rich PQE-1 proteins protectCaenorhabditis elegansneurons from huntingtin polyglutamine neurotoxicity. Proc Natl Acad Sci U S A 99 17131 - 17136    DOI : 10.1073/pnas.262544899
Parker JA , Metzler M , Georgiou J (2007) Huntingtininteracting protein 1 influences worm and mouse presynaptic function and protectsCaenorhabditis elegansneurons against mutant polyglutamine toxicity. J Neurosci 27 11056 - 11064    DOI : 10.1523/JNEUROSCI.1941-07.2007
Parker JA , Arango M , Abderrahmane S (2005) Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet 37 349 - 350    DOI : 10.1038/ng1534
Bates EA , Victor M , Jones AK , Shi Y , Hart AC (2006) Differential contributions ofCaenorhabditis eleganshistone deacetylases to huntingtin polyglutamine toxicity. J Neurosci 26 2830 - 2838    DOI : 10.1523/JNEUROSCI.3344-05.2006
Schapira AH , Jenner P (2011) Etiology and pathogenesis of Parkinson's disease. Mov Disord 26 1049 - 1055    DOI : 10.1002/mds.23732
Knight AL , Yan X , Hamamichi S (2014) The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models. Cell Metab 20 145 - 157    DOI : 10.1016/j.cmet.2014.04.017
Pasinelli P , Brown RH (2006) Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 7 710 - 723    DOI : 10.1038/nrn1971
Rosen DR , Siddique T , Patterson D (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362    DOI : 10.1038/362059a0
Cudkowicz M , McKenna‐Yasek D , Sapp P (1997) Epidemiology of mutations in superoxide dismutase in amyotrophic lateal sclerosis. Ann Neurol 41 210 - 221    DOI : 10.1002/ana.410410212
Bohni R , Riesgo-Escovar J , Oldham S (1999) Autonomous control of cell and organ size by CHICO, aDrosophilahomolog of vertebrate IRS1-4. Cell 97 865 - 875    DOI : 10.1016/S0092-8674(00)80799-0
Verdu J , Buratovich MA , Wilder EL , Birnbaum MJ (1999) Cell-autonomous regulation of cell and organ growth inDrosophilaby Akt/PKB. Nat Cell Biol 1 500 - 506    DOI : 10.1038/70293
Weinkove D , Neufeld TP , Twardzik T , Waterfield MD , Leevers SJ (1999) Regulation of imaginal disc cell size, cell number and organ size byDrosophilaclass I(A) phosphoinositide 3-kinase and its adaptor. Curr Biol 9 1019 - 1029    DOI : 10.1016/S0960-9822(99)80450-3
Leevers SJ , Weinkove D , MacDougall LK , Hafen E , Waterfield MD (1996) TheDrosophilaphosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J 15 6584 - 6594
Junger MA , Rintelen F , Stocker H (2003) TheDrosophilaforkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J Biol 2 20 -    DOI : 10.1186/1475-4924-2-20
Kramer JM , Davidge JT , Lockyer JM , Staveley BE (2003) Expression ofDrosophilaFOXO regulates growth and can phenocopy starvation. BMC Dev Biol 3 5 -    DOI : 10.1186/1471-213X-3-5
Puig O , Marr MT , Ruhf ML , Tjian R (2003) Control of cell number byDrosophilaFOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev 17 2006 - 2020    DOI : 10.1101/gad.1098703
Staveley BE , Ruel L , Jin J (1998) Genetic analysis of protein kinase B (AKT) inDrosophila. Curr Biol 8 599 - 602    DOI : 10.1016/S0960-9822(98)70231-3
Poltilove RM , Jacobs AR , Haft CR , Xu P , Taylor SI (2000) Characterization ofDrosophilainsulin receptor substrate. J Biol Chem 275 23346 - 23354    DOI : 10.1074/jbc.M003579200
Petruzzelli L , Herrera R , Arenas-Garcia R , Fernandez R , Birnbaum MJ , Rosen OM (1986) Isolation of aDrosophilagenomic sequence homologous to the kinase domain of the human insulin receptor and detection of the phosphorylatedDrosophilareceptor with an anti-peptide antibody. Proc Natl Acad Sci U S A 83 4710 - 4714    DOI : 10.1073/pnas.83.13.4710
Fernandez-Almonacid R , Rosen OM (1987) Structure and ligand specificity of theDrosophila melanogasterinsulin receptor. Mol Cell Biol 7 2718 - 2727    DOI : 10.1128/MCB.7.8.2718
Fernandez R , Tabarini D , Azpiazu N , Frasch M , Schlessinger J (1995) TheDrosophilainsulin receptor homolog: a gene essential for embryonic development encodes two receptor isoforms with different signaling potential. EMBO J 14 3373 - 3384
Marin-Hincapie M , Garofalo RS (1999) The carboxyl terminal extension of theDrosophilainsulin receptor homologue binds IRS-1 and influences cell survival. J Biol Chem 274 24987 - 24994    DOI : 10.1074/jbc.274.35.24987
Franke TF , Tartof KD , Tsichlis PN (1994) The SH2-like Akt homology (AH) domain of c-akt is present in multiple copies in the genome of vertebrate and invertebrate eucaryotes. Cloning and characterization of theDrosophila melanogasterc-akt homolog Dakt1. Oncogene 9 141 - 148
Cho KS , Lee JH , Kim S (2001) Drosophilaphosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway. Proc Natl Acad Sci U S A 98 6144 - 6149    DOI : 10.1073/pnas.101596998
Linassier C , MacDougall LK , Domin J , Waterfield MD (1997) Molecular cloning and biochemical characterization of aDrosophilaphosphatidylinositol-specific phosphoinositide 3-kinase. Biochem J 321 (Pt 3) 849 - 856    DOI : 10.1042/bj3210849
Brogiolo W , Stocker H , Ikeya T , Rintelen F , Fernandez R , Hafen E (2001) An evolutionarily conserved function of theDrosophilainsulin receptor and insulin-like peptides in growth control. Curr Biol 11 213 - 221    DOI : 10.1016/S0960-9822(01)00068-9
Gao X , Neufeld TP , Pan D (2000) DrosophilaPTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways. Dev Biol 221 404 - 418    DOI : 10.1006/dbio.2000.9680
Goberdhan DC , Paricio N , Goodman EC , Mlodzik M , Wilson C (1999) Drosophilatumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev 13 3244 - 3258    DOI : 10.1101/gad.13.24.3244
Huang H , Potter CJ , Tao W (1999) PTEN affects cell size, cell proliferation and apoptosis duringDrosophilaeye development. Development 126 5365 - 5372
Bai H , Kang P , Hernandez AM , Tatar M (2013) Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis inDrosophila. PLoS Genet 9 e1003941 -    DOI : 10.1371/journal.pgen.1003941
Hwangbo DS , Gershman B , Tu MP , Palmer M , Tatar M (2004) DrosophiladFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429 562 - 566    DOI : 10.1038/nature02549
Gronke S , Clarke DF , Broughton S , Andrews TD , Partridge L 2010 Molecular evolution and functional characterization ofDrosophilainsulin-like peptides. PLoS Genet 6 e1000857 -    DOI : 10.1371/journal.pgen.1000857
Broughton SJ , Piper MD , Ikeya T (2005) Longer lifespan, altered metabolism, and stress resistance inDrosophilafrom ablation of cells making insulin-like ligands. Proc Natl Acad Sci U S A 102 3105 - 3110    DOI : 10.1073/pnas.0405775102
Tatar M , Kopelman A , Epstein D , Tu MP , Yin CM , Garofalo RS (2001) A mutantDrosophilainsulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292 107 - 110    DOI : 10.1126/science.1057987
Clancy DJ , Gems D , Harshman LG (2001) Extension of life-span by loss of CHICO, aDrosophilainsulin receptor substrate protein. Science 292 104 - 106    DOI : 10.1126/science.1057991
Tu MP , Epstein D , Tatar M (2002) The demography of slow aging in male and femaleDrosophilamutant for the insulin-receptor substrate homologue chico. Aging Cell 1 75 - 80    DOI : 10.1046/j.1474-9728.2002.00010.x
Nielsen MD , Luo X , Biteau B , Syverson K , Jasper H (2008) 14-3-3 antagonizes FoxO to control growth, apoptosis and longevity inDrosophila. Aging Cell 7 688 - 699    DOI : 10.1111/j.1474-9726.2008.00420.x
Demontis F , Perrimon N (2008) FOXO/4E-BP signaling inDrosophilamuscles regulates organism-wide proteostasis during aging. Cell 143 813 - 825    DOI : 10.1016/j.cell.2010.10.007
Giannakou ME , Goss M , Junger MA , Hafen E , Leevers SJ , Partridge L (2004) Long-livedDrosophilawith overexpressed dFOXO in adult fat body. Science 305 361 -    DOI : 10.1126/science.1098219
Wessells RJ , Fitzgerald E , Cypser JR , Tatar M , Bodmer R (2004) Insulin regulation of heart function in aging fruit flies. Nat Genet 36 1275 - 1281    DOI : 10.1038/ng1476
Ford D , Hoe N , Landis GN (2007) Alteration ofDrosophilalife span using conditional, tissue-specific expression of transgenes triggered by doxycyline or RU486/Mifepristone. Exp Gerontol 42 483 - 497    DOI : 10.1016/j.exger.2007.01.004
Broeck JV (2001) Neuropeptides and their precursors in the fruitfly,Drosophila melanogaster. Peptides 22 241 - 254    DOI : 10.1016/S0196-9781(00)00376-4
Colombani J , Andersen DS , Léopold P (2012) Secreted peptide Dilp8 coordinatesDrosophilatissue growth with developmental timing. Science 336 582 - 585    DOI : 10.1126/science.1216689
Garelli A , Gontijo AM , Miguela V , Caparros E , Dominguez M (2012) Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation. Science 336 579 - 582    DOI : 10.1126/science.1216735
Cao C , Brown MR (2001) Localization of an insulin-like peptide in brains of two flies. Cell Tissue Res 304 317 - 321    DOI : 10.1007/s004410100367
Ikeya T , Galic M , Belawat P , Nairz K , Hafen E (2002) Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation inDrosophila. Curr Biol 12 1293 - 1300    DOI : 10.1016/S0960-9822(02)01043-6
Rulifson EJ , Kim SK , Nusse R (2002) Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 296 1118 - 1120    DOI : 10.1126/science.1070058
Lee KS , Kwon OY , Lee JH (2008) Drosophilashort neuropeptide F signalling regulates growth by ERK-mediated insulin signalling. Nat Cell Biol 10 468 - 475    DOI : 10.1038/ncb1710
Grönke S , Partridge L (2010) The functions of insulin-like peptides in insects; in IGFs: Local Repair and Survival Factors Throughout Life Span, Clemmons DR, Robinson I and Christen Y (eds) Springer 105 - 124
Nassel DR , Liu Y , Luo J (2015) Insulin/IGF signaling and its regulation inDrosophila. Gen Comp Endocrinol 221 255 - 266    DOI : 10.1016/j.ygcen.2014.11.021
Haselton A , Sharmin E , Schrader J , Sah M , Poon P , Fridell Y-WC (2010) Partial ablation of adultDrosophilainsulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance. Cell Cycle 9 3135 - 3143    DOI : 10.4161/cc.9.15.12458
Jeong DE , Artan M , Seo K , Lee SJ (2012) Regulation of lifespan by chemosensory and thermosensory systems: findings in invertebrates and their implications in mammalian aging. Front Genet 3 218 -    DOI : 10.3389/fgene.2012.00218
Wang MC , Bohmann D , Jasper H (2005) JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 121 115 - 125    DOI : 10.1016/j.cell.2005.02.030
Bauer JH , Chang C , Morris SNS (2007) Expression of dominant-negative Dmp53 in the adult fly brain inhibits insulin signaling. Proc Natl Acad Sci U S A 104 13355 - 13360    DOI : 10.1073/pnas.0706121104
Broughton S , Alic N , Slack C (2008) Reduction of DILP2 inDrosophilatriages a metabolic phenotype from lifespan revealing redundancy and compensation among DILPs. PLoS One 3 e3721 -    DOI : 10.1371/journal.pone.0003721
Okamoto N , Yamanaka N , Yagi Y (2009) A fat body-derived IGF-like peptide regulates postfeeding growth inDrosophila. Dev Cell 17 885 - 891    DOI : 10.1016/j.devcel.2009.10.008
Slaidina M , Delanoue R , Gronke S , Partridge L , L#233;opold P (2009) ADrosophilainsulin-like peptide promotes growth during nonfeeding states. Dev Cell 17 874 - 884    DOI : 10.1016/j.devcel.2009.10.009
Bai H , Kang P , Tatar M (2012) Drosophilainsulin‐like peptide‐6 (dilp6) expression from fat body extends lifespan and represses secretion ofDrosophilainsulin‐like peptide‐2 from the brain. Aging cell 11 978 - 985    DOI : 10.1111/acel.12000
Holzenberger M , Dupont J , Ducos B (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421 182 - 187    DOI : 10.1038/nature01298
Yuan R , Tsaih SW , Petkova SB (2009) Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8 277 - 287    DOI : 10.1111/j.1474-9726.2009.00478.x
Tazearslan C , Cho M , Suh Y (2012) Discovery of functional gene variants associated with human longevity: opportunities and challenges. J Gerontol A Biol Sci Med Sci 67 376 - 383    DOI : 10.1093/gerona/glr200